Synthesis and antiarrhythmic activity of disubstituted phenylpyridine derivative

A series of disubstituted phenylpyridine derivatives was synthesized and their antiarrhythmic effects against chloroform-induced ventricular arrhythmias in mice were examined. Among them, 2- and 3-[2-(3-aminobutyramido)-4-(2,2,2-trifluroethoxy)phenyl]pyri dines (23h, 24h) and 3-[2-(3-aminobutyramido)-4-ethoxyphenyl]pyridine (24i) showed potent antiarrhythmic activity. They had approximately twice the potency of mexiletine (III). Compound 24i was selected from this series as a candidate for further development; it was found to have a class I B electrophysiological character and to show a slow kinetic rate-dependent block (RDB) of the sodium channel in cardiac muscle.